Traumatic brain injury (TBI) affects over 1.7 million Americans each year and is the leading cause of death and disability in young children in the United States. For children with TBI, current treatment options are largely extrapolated from studies on adults, despite significant differences between pediatric and adult brains. Therefore, this proposal aims to specifically study pediatric injury, using clinically-relevant models of childhood disease. Specifically, we will focus on the role of astrocytes in pediatric TBI, a highly understudied area of research. It is well established that astrocytes in the brain and spinal cord play a major role in both acute and long term response to injury. Astrocytes associated with injured tissue, termed reactive astrocytes, are characterized by profound changes in protein expression leading to changes in the fundamental properties of these cells. Yet, little is known about the genetic regulation of the astrocytic injury response. This proposal seeks to address this question by examining the regulation of two essential functions of astrocytes following injury: the ability to buffer extracellular K+ ions and to regulate extracellular glutamate concentrations. These two astrocytic functions are largely mediated via the inwardly-rectifying potassium channel, Kir4.1, and the astrocytic glutamate transporter, GLT-1. In the adult spinal cord and brain, dysregulated K+ and glutamate homeostasis in the extracellular space leads to neuronal hyperexcitability, changes in synaptic physiology, and plasticity. Furthermore, both proteins are developmentally regulated with the most significant increases in expression in humans and rodents during early postnatal development at the peak of glutamatergic synaptogenesis, establishing an important role for these two proteins in the immature brain. This developmental period also correlates with the age group highest at risk for TBI. Despite the importance of these two proteins in brain function, very little is known regarding their regulation during development or in response to injury. Using a highly clinical relevant model of TBI, this proposal aims to specifically ask the following questions: 1) Following pediatric injury, is there persistent decrease in Kir4.1 and GLT-1, leading to neuronal hyperexcitability? 2) Is loss of these proteins a direct result of epigenetic modulation of gene transcription? 3) Can manipulation of DNA methylation using FDA-approved drugs reverse the loss of Kir4.1 and GLT-1 in pediatric injury models? This proposal seeks to enhance our understanding of the role of astrocytes, the most abundant cells in the CNS, in the pathophysiology of pediatric traumatic brain injury and abnormal brain development following injury. Results from these experiments could lead to novel therapeutic strategies using FDA-approved drugs for the treatment of TBI in pediatric patients.